Laquinimod is a compound which has been shown to be effective in the acute experimental autoimmune encephalomyelitis (aEAE) model (U.S. Pat. No. 6,077,851). Its chemical name is N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide, and its Chemical Registry number is 248281-84-7.
Laquinimod is a small, molecule having the following chemical structure:

The processes of synthesis of laquinimod and the preparation of its sodium salt are disclosed in U.S. Pat. No. 6,077,851. An additional process of synthesis of laquinimod acid, but not laquinimod sodium, having low levels of impurities disclosed in U.S. Pat. No. 6,875,869. U.S. Pat. No. 7,894,208 teaches a process for the preparation of laquinimod sodium which removes the impurities present after the salt formation step, thus resulting in a crystalline mixture of higher purity as well as a crystalline mixture having large particles, and good tapped and bulk density. Pharmaceutical compositions comprising laquinimod sodium are disclosed in PCT International Application Publication No. WO 2005/074899.
In the preparation of laquinimod sodium disclosed in U.S. Pat. No. 6,077,851, laquinimod acid was suspended in ethanol, and 5M sodium hydroxide solution was added. After stirring, the resulting precipitate was filtered, washed with ethanol, and dried. The method used to make laquinimod sodium in U.S. Pat. No. 6,077,851 is commonly referred to as a slurry-to-slurry salt formation.
In the slurry-to-slurry salt formation method of U.S. Pat. No. 6,077,851, the laquinimod sodium is not dissolved in solution. Any solid impurities, if present in the laquinimod sodium suspension, are therefore not removed by filtration.
U.S. Pat. No. 6,875,869 discloses a process of preparing the base compound laquinimod in high yield and low level of impurities. However, the process in U.S. Pat. No. 6,875,869 is only for synthesis of the base compound (lauqinimod acid) and not the salt. As such, the slurry-to-slurry salt formation process would still be needed to form the sodium salt.
U.S. Pat. No. 7,884,208 teaches an improved process for preparing laquinimod sodium resulting in crystals of higher purity as well as crystals having improved crystalline characteristics, e.g., comprising no more than 2 ppm of a heavy metal and having higher tapped density. In the process disclosed in U.S. Pat. No. 7,884,208 in Examples 13-17, laquinimod sodium is dissolved in water to form an aqueous solution; the aqueous solution is concentrated; and then a water-miscible anti-solvent is added to the concentrated solution to form laquinimod sodium crystals. The process of U.S. Pat. No. 7,884,208 removes the impurities after salt formation, thus resulting in laquinimod sodium of higher purity than the laquinimod sodium produced directly from the “slurry to slurry” process of U.S. Pat. No. 6,077,851.